Avacopan for ANCA-associated vasculitis with hypoxic pulmonary haemorrhage.

BACKGROUND AND HYPOTHESIS: Pulmonary haemorrhage with hypoxia caused by ANCA-associated vasculitis (AAV) has a high early mortality. Avacopan, an oral C5a receptor antagonist, is an approved treatment for AAV, but patients with pulmonary haemorrhage requiring invasive pulmonary ventilation support were excluded from the ADVOCATE trial. METHODS: A retrospective, observational, multicentre case series of AAV patients with hypoxic pulmonary haemorrhage, requiring oxygen support or mechanical ventilation, who received avacopan. RESULTS: Eight patients (62.5% female), median age 64 years (range 17-80), seven with kidney involvement, median glomerular filtration rate (GFR) 11 (range 5-99) ml/min per 1.73m2, were followed for a median of 6 months from presentation. Seven were newly diagnosed (87.5%), five were MPO-ANCA and three PR3-ANCA positive. All had hypoxia, four requiring mechanical ventilation (three invasive and one non-invasive). Intensive care unit (ICU) stay for the four patients lasted a median of 9 days (range 6-60). Four received rituximab and cyclophosphamide combination, three rituximab and one cyclophosphamide. Four underwent plasma exchange and one received two months of daily extracorporeal membrane oxygenation (ECMO) therapy. Following the initiation of avacopan after a median of 10 days (range 2-40), pulmonary haemorrhage resolved in all patients, even two who had one month of refractory pulmonary haemorrhage prior to avacopan. Additionally, after one month, the median prednisolone dose was 5 mg/day (range 0-50), with three patients successfully discontinuing steroid use. Two patients suffered serious infections, two discontinued avacopan, one permanently due to a rash and one temporarily after three months due to neutropenia. All patients survived and no re-hospitalization occurred. CONCLUSION: We report the use of avacopan as a component of the treatment for pulmonary haemorrhage with hypoxia in AAV. Despite the life-threatening presentations all patients recovered, but attribution of the positive outcomes to avacopan is limited by the concomitant therapies and retrospective observational design.

Relapse after cessation of weekly tocilizumab for giant cell arteritis: a multicentre service evaluation in England.

OBJECTIVES: The National Health Service in England funds 12 months of weekly subcutaneous tocilizumab (qwTCZ) for patients with relapsing or refractory giant cell arteritis (GCA). During the COVID-19 pandemic, some patients were allowed longer treatment. We sought to describe what happened to patients after cessation of qwTCZ. METHODS: Multicentre service evaluation of relapse after stopping qwTCZ for GCA. The log-rank test was used to identify significant differences in time to relapse. RESULTS: 336 GCA patients were analysed from 40 centres, treated with qwTCZ for a median (interquartile range, IQR) of 12 (12-17) months. At time of stopping qwTCZ, median (IQR) prednisolone dose was 2 (0-5) mg/day. By 6, 12 and 24 months after stopping qwTCZ, 21.4%, 35.4% and 48.6% respectively had relapsed, requiring an increase in prednisolone dose to a median (IQR) of 20 (10-40) mg/day. 33.6% of relapsers had a major relapse as defined by EULAR. Time to relapse was shorter in those that had previously also relapsed during qwTCZ treatment (P = 0.0017); in those not in remission at qwTCZ cessation (P = 0.0036); and in those with large vessel involvement on imaging (P = 0.0296). Age ≥65, gender, GCA-related sight loss, qwTCZ treatment duration, TCZ taper, prednisolone dosing, and conventional synthetic DMARD use were not associated with time to relapse. CONCLUSION: Up to half our patients with GCA relapsed after stopping qwTCZ, often requiring a substantial increase in prednisolone dose. One third of relapsers had a major relapse. Extended use of TCZ or repeat treatment for relapse should be considered for these patients.

Quality standards for the care of people with giant cell arteritis in secondary care.

OBJECTIVE: GCA is the commonest primary systemic vasculitis in adults, with significant health economic costs and societal burden. There is wide variation in access to secondary care GCA services, with 34% of hospitals in England not having any formal clinical pathway. Quality standards provide levers for change to improve services. METHODS: The multidisciplinary steering committee were asked to anonymously put forward up to five aspects of service essential for best practice. Responses were qualitatively analysed to identify common themes, subsequently condensed into domain headings, and ranked in order of importance. Quality standards and metrics for each domain were drafted, requiring a minimum 75% agreement. RESULTS: 13 themes were identified from the initial suggestions. Nine quality standards with auditable metrics were developed from the top 10 themes. Patient Access, glucocorticoid use, pathways, ultrasonography, temporal artery biopsy, PET scan access, rheumatology/ophthalmology expertise, education, multidisciplinary working have all been covered in these quality standards. Access to care is a strand that has run through each of the developed standards. An audit tool was developed as part of this exercise. CONCLUSION: These are the first consensus auditable quality standards developed by clinicians from rheumatology and ophthalmology, nursing representatives and involvement of a patient charity. We hope that these standards will be adopted by commissioning bodies to provide levers for change from the improvement of patient care of individuals with GCA.

Reliability assessment of the definition of ultrasound enthesitis in SpA: results of a large, multicentre, international, web-based study.

OBJECTIVES: To investigate the reliability of the OMERACT US Task Force definition of US enthesitis in SpA. METHODS: In this web exercise, based on the evaluation of 101 images and 39 clips of the main entheses of the lower limbs, the elementary components included in the OMERACT definition of US enthesitis in SpA (hypoechoic areas, entheseal thickening, power Doppler signal at the enthesis, enthesophytes/calcifications, bone erosions) were assessed by 47 rheumatologists from 37 rheumatology centres in 15 countries. Inter- and intra-observer reliability of the US components of enthesitis was calculated using Light's kappa, Cohen's kappa, Prevalence And Bias Adjusted Kappa (PABAK) and their 95% CIs. RESULTS: Bone erosions and power Doppler signal at the enthesis showed the highest overall inter-reliability [Light's kappa: 0.77 (0.76-0.78), 0.72 (0.71-0.73), respectively; PABAK: 0.86 (0.86-0.87), 0.73 (0.73-0.74), respectively], followed by enthesophytes/calcifications [Light's kappa: 0.65 (0.64-0.65), PABAK: 0.67 (0.67-0.68)]. This was moderate for entheseal thickening [Light's kappa: 0.41 (0.41-0.42), PABAK: 0.41 (0.40-0.42)], and fair for hypoechoic areas [Light's kappa: 0.37 (0.36-0.38); PABAK: 0.37 (0.37-0.38)]. A similar trend was observed in the intra-reliability exercise, although this was characterized by an overall higher degree of reliability for all US elementary components compared with the inter-observer evaluation. CONCLUSIONS: The results of this multicentre, international, web-based study show a good reliability of the OMERACT US definition of bone erosions, power Doppler signal at the enthesis and enthesophytes/calcifications. The low reliability of entheseal thickening and hypoechoic areas raises questions about the opportunity to revise the definition of these two major components for the US diagnosis of enthesitis.

Reliability assessment of ultrasound muscle echogenicity in patients with rheumatic diseases: Results of a multicenter international web-based study.

Objectives: To investigate the inter/intra-reliability of ultrasound (US) muscle echogenicity in patients with rheumatic diseases. Methods: Forty-two rheumatologists and 2 radiologists from 13 countries were asked to assess US muscle echogenicity of quadriceps muscle in 80 static images and 20 clips from 64 patients with different rheumatic diseases and 8 healthy subjects. Two visual scales were evaluated, a visual semi-quantitative scale (0-3) and a continuous quantitative measurement ("VAS echogenicity," 0-100). The same assessment was repeated to calculate intra-observer reliability. US muscle echogenicity was also calculated by an independent research assistant using a software for the analysis of scientific images (ImageJ). Inter and intra reliabilities were assessed by means of prevalence-adjusted bias-adjusted Kappa (PABAK), intraclass correlation coefficient (ICC) and correlations through Kendall's Tau and Pearson's Rho coefficients. Results: The semi-quantitative scale showed a moderate inter-reliability [PABAK = 0.58 (0.57-0.59)] and a substantial intra-reliability [PABAK = 0.71 (0.68-0.73)]. The lowest inter and intra-reliability results were obtained for the intermediate grades (i.e., grade 1 and 2) of the semi-quantitative scale. "VAS echogenicity" showed a high reliability both in the inter-observer [ICC = 0.80 (0.75-0.85)] and intra-observer [ICC = 0.88 (0.88-0.89)] evaluations. A substantial association was found between the participants assessment of the semi-quantitative scale and "VAS echogenicity" [ICC = 0.52 (0.50-0.54)]. The correlation between these two visual scales and ImageJ analysis was high (tau = 0.76 and rho = 0.89, respectively). Conclusion: The results of this large, multicenter study highlighted the overall good inter and intra-reliability of the US assessment of muscle echogenicity in patients with different rheumatic diseases.

Myopericarditis as a presentation of eosinophilic granulomatosus with polyangiitis (EGPA).

A 60-year-old woman was admitted to the hospital with worsening dyspnoea, cough and chest pain. This was on a background of weight loss, decreased appetite, mononeuritis multiplex, chronic eosinophilia and a single episode of a non-blanching rash. Investigations demonstrated a raised troponin and ischaemic changes on ECG, and she was therefore initially treated for a presumed myocardial infarction. However, her symptoms failed to improve with treatment for the acute coronary syndrome. A coronary angiogram revealed no significant flow-limiting disease, and further investigations yielded confirmation of raised eosinophils and a positive perinuclear antineutrophil cytoplasmic antibody test. An echocardiogram demonstrated a pericardial effusion, and subsequent cardiac magnetic resonance features were compatible with myopericarditis. In light of these findings, the patient was diagnosed with eosinophilic granulomatous with polyangiitis and commenced on high-dose intravenous methylprednisolone and cyclophosphamide. She made an excellent recovery and remains in remission on azathioprine and a tapering dose of corticosteroids.

Biosimilars: From Extrapolation into Off Label Use.

BACKGROUND: Biologic drugs have revolutionised the management of many inflammatory conditions. Patent expirations have stimulated development of highly similar but non-identical molecules, the biosimilars. Extrapolation of indications is a key concept in the development of biosimilars. However, this has been met with concerns around mechanisms of action, equivalence in efficacy and immunogenicity, which are reviewed in this article. METHODS: Narrative overview composed from literature search and the authors' experience. Literature search included Pubmed, Web of Science, and online document archives of the Food and Drug Administration and European Medicines Agency. RESULTS: The concepts of biosimilarity and extrapolation of indications are revisited. Concerns around extrapolation are exemplified using the biosimilar infliximab, CT-P13, focusing on mechanisms of action, immunogenicity and trial design. The opportunities and cautions for using biologics and biosimilars in unlicensed inflammatory conditions are reviewed. CONCLUSIONS: Biosimilars offer many potential opportunities in improving treatment access and increasing treatment options. The high cost associated with marketing approval means that many bio-originators may never become licenced for rarer inflammatory conditions, despite clinical efficacy. Biosimilars, with lower acquisition cost, may improve access for off-label use of biologics in the management of these patients. They may also provide opportunities to explore off-label treatment of conditions where biologic therapy is less established. However, this potential advantage must be balanced with the awareness that off-label prescribing can potentially expose patients to risky and ineffective treatments. Post-marketing surveillance is critical to developing long-term evidence to provide assurances on efficacy as well as safety.

Fibromyalgia in Behçet's disease: a narrative review.

INTRODUCTION: Fibromyalgia is characterised by chronic widespread pain and tenderness. It has often been reported to occur concomitantly with chronic rheumatological conditions. Behçet's disease is a chronic relapsing, multisystem, autoinflammatory disease. There is only limited understanding of a potential relationship between fibromyalgia and Behçet's disease. AIM: Given the potential detrimental influence of pain on the outcome of chronic disease, the aim of this narrative review is to gain an understanding of the incidence and presentation of fibromyalgia in Behçet's disease. METHODS: Electronic databases Scopus, Medline, PubMed and UpToDate were searched. RESULTS: A total of 269 studies were identified, and limitations and exclusion/inclusion criteria were applied to ensure accurate and comparable selection of studies; four studies were selected. All cases were assessed for the presence of fibromyalgia according to the 1990 or 2010 diagnostic criteria of the American College of Rheumatology, with Behçet's disease diagnosed according to the International Study Group (ISG) for Behçet's disease criteria. A higher prevalence of fibromyalgia (5.7-37.1%) was reported in Behçet's disease compared to that of the general population (2.9-4.7%). DISCUSSION: While an increased prevalence of fibromyalgia was found in patients with Behçet's disease, this needs to be considered within the context of limited available evidence. The potential impact of these conditions on the disease activity of each other is not clear and may require a prospective study. CONCLUSION: Fibromyalgia appears to be more prevalent in those with Behçet's disease than would be expected in the overall population. Significance: This review provides some evidence that fibromyalgia is more prevalent in those with Behçet's disease. To ensure appropriate patient treatment choices, it is important that both conditions are diagnosed where they co-exist.

Behcet's disease.

Behçet's disease (BD) is a chronic relapsing and remitting vasculitis of unknown aetiology. It has the capacity to affect almost all organ systems because of its potential to involve both arteries and veins of all sizes, resulting in significant organ-threatening morbidity and mortality. Traditionally known as the 'silk road' disease, it has a worldwide occurrence. The aetiopathological mechanisms of disease development in BD remain poorly understood, but genome wide studies show human leukocyte antigen and non-human leukocyte antigen associations. Environmental influences and genetic factors may have a role in the aetiopathogenetic mechanisms that lead to development of the disease, indicating the autoimmune and auto-inflammatory nature of BD. The evidence base for treatment is limited but new knowledge is emerging and current treatment options range from symptomatic treatment, through to non-biological and biological immunosuppressive drugs, to cover the spectrum of clinical manifestations.

Mavrilimumab, a human monoclonal GM-CSF receptor-α antibody for the management of rheumatoid arthritis: a novel approach to therapy.

INTRODUCTION: Mavrilimumab , formerly known as CAM-3001, a GM-CSF receptor-α antibody, is the first human monoclonal antibody to be used in Phase II studies (2011) to modulate the innate immunity pathway targeting GM-CSF signaling in moderate rheumatoid arthritis (RA). AREAS COVERED: Analysis of available clinical trial data on GM-CSF receptor-α antibody and medical literature search using MEDLINE for molecular mechanisms of pathogenesis of RA and its treatment forms the basis of this expert opinion review. The mavrilimumab Phase II double blind, randomized, placebo-controlled ascending dose trial demonstrated statistically significant achievement of primary and secondary end points in patients with moderate RA. The trial demonstrated significant clinical benefit in the 100 mg mavrilimumab cohort compared to the placebo group. EXPERT OPINION: The novel molecular targeting mechanism of mavrilimumab together with its demonstrated clinical efficacy, tolerability and safety profile in Phase II clinical trials in moderate RA, suggests significant potential utility for this drug to induce clinical remission, reduce flares and improve morbidity and mortality in patients with RA.

Myopericarditis in giant cell arteritis: case report of diagnostic dilemma and review of literature.

Giant cell arteritis (GCA), also known as granulomatous arteritis is a systemic vasculitis mainly affecting extra cranial branches of carotid arteries. It can rarely affect other vascular beds causing thoracic aorta aneurysm, dissection and rarely cause myocardial infarction through coronary arteritis. It can cause considerable diagnostic dilemma due to varied clinical presentations. The authors report an illustrative case of a 70-year-old woman with GCA who developed symptoms suggestive of acute myocardial infarction with chest pain, localised ST-T changes and echocardiographic left ventricular dysfunction. However, cardiac troponin T biomarkers and coronary angiography were normal. Her symptoms subsided with steroid treatment. Cardiac symptoms at first presentation of GCA are unusual.

Simultaneous bilateral posterior fracture dislocation of the shoulders in a young man with unexpected severe vitamin D deficiency.

Simultaneous bilateral posterior fracture dislocation of the shoulders is a rare clinical presentation. There are three main etiologies described in the literature. Given that it presents with relatively uncharacteristic symptoms, in many cases it is diagnosed late. We present the case of a man who was admitted with bilateral posterior fracture dislocation of the shoulders following a seizure. Investigations revealed severe vitamin D deficiency as the principal contributory factor to his injury. This is an important association because failure to recognize and treat this can result in significant morbidity in susceptible groups.

An unusual case of back pain: A large Pheochromocytoma in an 85 year old woman.

INTRODUCTION: Low back ache is a common complaint in the elderly and in the absence of red flag symptoms can be easily dismissed as benign. Pheochromocytoma presenting as back pain is unusual and to our knowledge, only two previous cases have been reported in the literature with back pain as the 'only' presenting symptom. CASE PRESENTATION: We illustrate the case of an 85 year-old woman who presented with a 6 month history of back pain due to a very large Pheochromocytoma. This was incidentally picked up during a routine Lumbar spine plain radiograph and was noted to be a large Pheochromocytoma occupying the whole of the left abdomen. She required an open adrenalectomy to remove the large left adrenal tumour weighing 2.3 kg. CONCLUSION: Pheochromocytoma can present as a mimic of musculoskeletal conditions and hence due care should be exercised in assessing such presentations both in the young and elderly patients. Our patient is different from the other reported cases, as she is an 85 year-old and 'back pain' can be easily dismissed without investigating in such age groups, thereby missing serious conditions.

Methyl iodide poisoning presenting as a mimic of acute stroke: a case report.

INTRODUCTION: Stroke mimics are usually non-vascular disease processes. These raise the possibility of a stroke and are common in clinical practice. It is necessary to distinguish these mimics in order to provide early and appropriate management, as well as reduce possible harm on our patient. CASE PRESENTATION: We report the case of a 50-year-old Caucasian man who developed symptoms suggestive of posterior circulation stroke after he was exposed to methyl iodide at his workplace. Results of stroke investigations of our patient were negative, and a detailed occupational history clinched the diagnosis. Acute presentation with a stroke-like picture is rare in cases of methyl iodide poisoning. We have attempted to discuss the differential diagnosis of stroke mimics through a review of literature. CONCLUSION: Stroke mimics are difficult to diagnose in an emergency room situation and may be initially treated as stroke. This case report underlines the importance of history taking, especially occupational history, in the differential diagnosis of stroke. We also stress the need to recognize mimics at presentation in order to arrive at an early and appropriate management of patients.